medwireNews: Findings from a systematic review and meta-analysis indicate that the incidence of herpes zoster among rheumatoid arthritis patients treated with Janus kinase (JAK) inhibitors is higher than expected in this population, and baricitinib is associated with a significantly increased risk.

However, the researchers note that absolute rates of serious infection were “low” overall.

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The meta-analysis included 11 studies (n=5888 participants in total) investigating tofacitinib at the approved dose of 5 mg twice daily, six studies (n=3520) of baricitinib at the approved dose of 4 mg once daily, and four trials of upadacitinib (n=1736) at the anticipated future licensed dose of 15 mg once daily. Treatment duration ranged from 6 weeks to 1 year, and the majority of trials included patients with an inadequate response to DMARDs.

As reported in Rheumatology, 51 cases of herpes zoster infection occurred among patients treated with tofacitinib over 2032 patient exposure–years (PEY), while 26 cases occurred in baricitinib-treated patients over 822 PEY and four occurred in upadacitinib-treated patients over 166 PEY, translating into estimated incidence rates of 2.51, 3.16, and 2.41 per 100 person–years, respectively.

By comparison, there were 17 cases of herpes zoster in the pooled placebo group over 1398 PEY, giving an estimated incidence rates of 1.22 per 100 person–years.

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Katie Bechman (Kings College London, UK) and colleagues note that the incidence of herpes zoster among JAK inhibitor-treated patients was “higher than expected in the RA population.” Patients treated with baricitinib had a significantly higher risk for herpes zoster than those given placebo (incidence rate ratio [IRR]=2.86), but those in the tofacitinib and upadacitinib groups did not.

The team says that baricitinib was associated with the highest herpes zoster risk and upadacitinib the lowest when the surface under the cumulative ranking curve method was used, albeit that there were “[h]igh levels of uncertainty in the risk estimates.”

Despite the elevated incidence of herpes zoster associated with JAK inhibitors, the study authors report low overall incidence rates for serious infection, at 1.97, 3.16, 3.02, and 2.50 per 100 person–years in the tofacitinib, baricitinib, upadacitinib, and pooled placebo groups, respectively. The IRRs for serious infection relative to placebo were not statistically significant for any of the JAK inhibitors.

“The most characteristic infectious complication with JAK [inhibitors] has been the reactivation of [varicella zoster virus],” and “[o]ur meta-analysis confirms this signal,” write Bechman and colleagues.

The researchers caution that second-generation JAK inhibitors such as filgotinib, decernotinib, and peficitinib were excluded from their analysis as there were no published phase III trials for these drugs at the time the analysis was carried out.

“The imminent publications of active phase III trials with the other JAK [inhibitors] and data from post-marketing surveillance by drug registries may provide new insights into the differential risk of infections with JAK inhibition, and the mechanisms behind the association with [herpes zoster],” they conclude.